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Abstract

Background

Vitamin D deficiency is a re-emerging epidemic, especially in minority populations.
Vitamin D is crucial not only for bone health but for proper brain development and
functioning. Low levels of vitamin D are associated with depression, seasonal affective
disorder, and schizophrenia in adults, but little is known about vitamin D and mental
health in the pediatric population.

Methods

One hundred four adolescents presenting for acute mental health treatment over a 16-month
period were assessed for vitamin D status and the relationship of 25-OH vitamin D
levels to severity of illness, defined by presence of psychotic features.

Conclusions

Vitamin D deficiency and insufficiency are both highly prevalent in adolescents with
severe mental illness. The preliminary associations between vitamin D deficiency and
presence of psychotic features warrant further investigation as to whether vitamin
D deficiency is a mediator of illness severity, result of illness severity, or both.
Higher prevalence of vitamin D deficiency but no greater risk of psychosis in African
Americans, if confirmed, may have special implications for health disparity and treatment
outcome research.

Keywords:

Vitamin D; Adolescents; Deficiency; Psychosis

Background

Vitamin D deficiency is endemic across the life span and in diverse populations throughout
the world [1]. Contributing factors are lack of exposure to sunlight and insufficient dietary intake;
individuals with darker skin are at higher risk due to low cutaneous synthesis and
dairy-poor diets. In a study of healthy Northeastern US adolescents, more than 90%
of African American teens and 55% of all teens had low vitamin D [2]. The National Health and Nutritional Examination Survey (NHANES 2001–2004) found
an overall US prevalence of vitamin D insufficiency in adolescents of 61%, with 9%
deficient [3].

Vitamin D is well recognized as essential for intestinal calcium absorption, serum
calcium homeostasis, optimal skeletal development, and the prevention of rickets and
osteoporosis [4]. The importance of vitamin D to the CNS in both healthy and psychiatric populations
is less well-appreciated and is vastly understudied compared to its known impact on
bone health. Vitamin D receptors are present throughout the brain, and D-deficiency
is associated with negative CNS effects in animal studies [5]. Vitamin D receptors and activating enzymes are particularly prominent in the hypothalamus
and substantia nigra, and are involved in glucocorticoid signaling in hippocampal
cells. Depletion models show maternal offspring with abnormal brain shape, cell number,
and reduced neurotropic factors and receptors. Vitamin D receptor animal knock-out
models show increased anxiety, decreased activity, and muscular and motor impairments,
resembling phenotypic models of depression. Vitamin D is neuroprotective to hippocampal
cells, through regulating calcium ion channels and activating PKC and mapPK pathways.

Clinical studies reinforce the significance of this basic work. A Finnish cohort supplemented
with prenatal and infant vitamin D demonstrated reduced adult risk for schizophrenia
[6]. Low vitamin D levels were found to correlate with major depression [7] and premenstrual mood symptoms in women [8], and mood disorders and cognitive impairment in older adults [9]. Two randomized controlled trials (RCT) have shown that raising vitamin D levels
improved depression. The first study examined phototherapy vs. vitamin D supplementation
for seasonal affective disorder, and found a positive effect for vitamin D via either
supplementation or phototherapy within one month [10]. Another RCT of overweight and obese subjects, at greater risk for low vitamin D
than those of normal weight, found higher levels of depression with low vitamin D;
supplementation resulted in significant improvement in depressive symptoms after one
year [11]. To the best of our knowledge, there have been no published studies examining vitamin
D deficiency and the presence of psychosis in adolescents.

We hypothesized that, in severely mentally ill adolescents, defined as adolescents
requiring either inpatient or partial hospitalization, 1) rates of vitamin D insufficiency
and deficiency would be greater than those documented in general US populations, and
2) lower vitamin D levels would be associated with mental illness severity, defined
as presence of psychotic features.

Methods and Materials

Ethics

The University of Rochester Research Subject Review Board approved the retrospective
chart review study.

Participants

The study population included 75 females and 29 males aged 12 to 18 years admitted
to the Strong Behavioral Health Child and Adolescent Acute Inpatient Service or Partial
Hospitalization Service (CAPHS), Department of Psychiatry, University of Rochester,
NY, between October 2008-February 2010 who had serum 25-OH vitamin D levels collected
on routine admission laboratory testing as part of a quality improvement initiative.

Data collection

Charts were identified by a clinical admission database of the service. Diagnostic
evaluations and symptom reports from parents/legal guardians and adolescents were
extracted from medical records for the period of clinical care.

Patient-reported psychosis and potentially related variables

Psychotic symptoms, defined as hallucinations, paranoia, or delusions, were documented
on standardized admission assessment forms by the emergency room psychiatrist and
the admitting attending. They were categorized dichotomously as yes/no by the second
author (TLF), who was blinded to both the purpose of the study and to vitamin D levels
until after record extraction was completed. Other variables examined included: race,
month of admission/vitamin D level, insurance status, urban/suburban/rural residence,
inpatient/partial hospital outpatient, clinical DSM-IV diagnosis, smoking status,
age of onset of mental illness, admitting medications, past medications, and immediate
and extended family psychiatric and medical history.

Vitamin D laboratory analysis and categorical definitions

Vitamin D 25-OH (25OHD) levels were analyzed by chemiluminescent immunoassay at ARUP
laboratories, SLC, Utah, and recorded as normal if >30 ng/ml, insufficient if 20–30 ng/ml,
and deficient if <20 ng/ml, as per expert guidelines [12].

Statistical analyses

Continuous data were graphically inspected for distributional assumptions; comparisons
between the normal, insufficient, and deficient vitamin D groups were evaluated by
ANOVAs (with t-tests subsequent to the overall analysis), Wilcoxon rank sum test,
χ², or Fisher’s exact test, as appropriate to the data. The relationship of vitamin
D levels and psychosis was assessed with an ANOVA type design and the association
of psychosis with vitamin D level groups with logistic regression models, assessing
race as well as vitamin D level groups in a multivariate model. All analyses were
carried out using SAS 9.2 on a Windows 7 platform.

Results

Vitamin D deficiency prevalence and association with psychosis

Thirty-five (33.7%) adolescents were vitamin D deficient (<20 ng/ml), and an additional
40 (38.4%) were vitamin D insufficient (20–30 ng/ml). Of those with vitamin D deficiency,
40% had psychotic features compared to only 16% of the sample who were not vitamin
D deficient (p < 0.007). Those with D deficiency were 3½ times more likely to have
psychotic features (OR 3.52, CI 1.38-8.95, 1df). Of those with normal vitamin D status,
79% (N = 23/29) did not have psychotic features.

Demographic and other related variable differences

A comparison of demographic variables between adolescents with insufficient, deficient,
and normal 25-OH D levels is presented in Table 1.

Racial differences

Those who were deficient were more likely to be black or Asian (Figure 1) and have psychotic features (Figure 2). Figure 3 displays the association of 25-OH vitamin D and the interaction of race and psychosis.
All groups showed lower 25-OH D levels in the presence of psychosis including Asians
who were all deficient. Asian (N = 5) and biracial (N = 7) categories were combined
into the “Other” category and Hispanic/Latino ethnicity (N = 1) was combined with
Caucasian in the linear modeling that was conducted. Odds ratio comparisons for presence
of psychosis with vitamin D deficiency as well as potential covariates, including
race and medication exposure, are depicted in Table 2. Psychosis was independently related to race for the “other” group (Asian and biracial
individuals) vs. white group, but not for black vs. white groups, nor significantly
associated for other vs. blacks. The association of psychosis and vitamin D level
was significant overall in the univariate and multivariable analyses. Of added interest
was the association of psychosis with Vitamin D levels and race (Table 3). While race and vitamin D levels were associated, race and psychosis were not associated
adjusting for vitamin D levels.

Figure 3.Association of psychosis, race, and interaction of psychosis and race on vitamin D
level expressed as continuous data. Y-axis displays 25OH-D levels in ng/mL; left vs. right side of figure denotes mean
25OHD levels without and with psychosis by race.

Family history, medication exposure, and seasonal differences

Immediate family history of psychosis and current antidepressant exposure were also
independently related to psychosis. Rates of vitamin D insufficiency and deficiency
rose from December through March, peaking in March, as would be expected. No seasonal
effects, however, were statistically detected (p = 0.14), possibly due to both latitude
and high rates of overall deficiency and insufficiency.

Discussion

This is the first report of an association between vitamin D deficiency in adolescents
and severity of mental illness, defined as presence of psychotic features. These findings
are similar to a cross-sectional study also linking vitamin D deficiency and adult
psychosis [13]. In a study of over 1,000 adults from combined cohorts of a longitudinal evaluation
of severe mental illness and a population-based sample from the Oslo Health Study,
vitamin D levels and presence of psychosis were compared between native Norwegians
and dark-complexion immigrants to Norway. Prevalence of vitamin D deficiency and insufficiency
in immigrants with psychosis was 80%, similar to the 72% in our sample of severely
mentally ill adolescents. Additionally, 43% of the Oslo community population with
psychosis met criteria for vitamin D deficiency, also similar to the 40% of this teen
sample with psychosis. In the adult epidemiologic sample, disorientation on the PANSS,
weight loss, and lack of physical energy correlated with lower 25-OH D levels after
controlling for major depression. Demographics, level of functioning, lifestyle habits,
and BMI were not associated with vitamin D levels.

Our findings also agree with an unpublished 2011 report of a child and adolescent
psychiatric population residing in the Pacific Northwest. Using the same definitions
of deficiency, insufficiency, and normal ranges as in the current study, 21% of 67
youth with severe psychiatric symptoms residing in 2 Oregon residential treatment
programs had vitamin D deficiency, vs. 14% of a comparable NHANES sample. For the
children with psychotic disorders, the prevalence of vitamin D deficiency was 43%
[14]. The overall mean 25-OH D level was 28.9 ng/mL, with 2/3 of the patients falling
below the normal range; mean 25-OHD in the youth with psychotic disorders was 26.47 ng/mL
(SD12.42). Another group of psychiatric inpatient Parisian adolescents (N = 136) were
also found to be largely vitamin D-deficient (72.4%), with the mean 25-OHD value 15–16 ng/mL,
lower in blacks and North Africans [15]. No differences in mean levels were found between those taking or not taking antipsychotics,
indicating that antipsychotics may not lower vitamin D absorption.

The prevalence of vitamin D deficiency in our sample of acutely mentally ill adolescents
is also greater than the high rates observed in U.S. community adolescent populations
(34% vs. NHANES 9%)[3] and in Australian adult private psychiatric inpatients (vitamin D deficiency 11%,
defined as <25 nmol/L, or 10 ng/mL) [16]. The latter study found a 29% difference between mean levels in patients vs. controls.
Our higher prevalence rates of deficiency and insufficiency may be in part due to
the latitude of Rochester, NY, 43.145 degrees N. Paris, France is 48.51 N, and Geelong,
Australia 38.10 S. Except during summer months, skin makes negligible vitamin D from
sunlight at latitudes above 37 degrees north or below 37 degrees south.

Race, ethnicity, dietary intake and sunlight exposure

Dietary intake and sunlight exposure as sources of vitamin D are influenced by race.
The NHANES found poor dietary intake of vitamin D and lower exercise in older African
American and female Hispanic adolescents. Although not fully comparable due to different
methodologies, our mentally ill non-Caucasian population also demonstrates more vitamin
D deficiency, and for Asians and biracial subjects a greater rate of psychosis, but
not after adjusting for vitamin D level. Small clinical studies to date suggest potential
for a causal link between low vitamin D and mood disorders [8-11,16,26], necessitating that randomized controlled trials in carefully defined populations
of interest be performed to better characterize the relationship between vitamin D
deficiency and risk for depression and psychosis.

Alternate hypotheses

In addition to the possibility that vitamin D deficiency contributes to vulnerability
to psychosis, other nutritional factors may play a role: adolescents eating a diet
low in dairy products may also consume less of other nutrient-rich foods, including
those with essential fatty acids. Adverse omega-3:omega-6 fatty acid ratios and/or
other dietary micronutrient deficiencies that are commonly associated with vitamin
D deficiency such as vitamin B12 may also contribute to emergence of psychotic symptoms.

Implications for future research in psychiatry

Effects on mental illness

If a prospective association between psychotic features and vitamin D deficiency is
confirmed, outstanding issues include: 1) how vitamin D affects monoamine function
and the HPA axis and immune responses to stress and symptom production, 2) whether
supplementation can be protective against incident depression or psychosis and their
recurrence, and 3) whether supplementation improves symptoms in those with clinically
diagnosed depression or psychosis, especially in populations with darker skin [26]. An open-label Swedish case-series suggests that depression is improved by vitamin
D supplementation in adolescents [27]. Prevention studies in high-risk offspring would be highly novel. Thus, future studies
could target both prevention of mental and comorbid physical illness, focusing on
disparity and somatic treatment augmentation.

Importance to overall health in psychiatric populations

Normalizing vitamin D levels warrants study in those with severe mental illness to
determine whether, and at what dose, vitamin D helps protect against metabolic side
effects from psychopharmacologic treatment or reduces the development of comorbid
physical illnesses such as diabetes, cardiovascular disease, and osteoporosis. Low
vitamin D is associated with greater BMI, insulin resistance, and systolic blood pressure,
lower HDL-C in obese adolescents and adults, and lower final height in young adult
women [3,28-31]. Vitamin D status may be especially important in those with serious mental illness
as they develop poorer metabolic health at earlier ages. Optimal vitamin D levels
also may protect against several different cancers (breast, colon, pancreas, and prostate),
and autoimmune disorders (lupus, multiple sclerosis, and Type I diabetes) [32]. Molecular mechanisms of vitamin D that are protective against cancer include reducing
cellular oxidative stress [33]. Vitamin D supplementation may thus represent a low-cost population-based intervention
capable of reducing utilization of more intensive physical and mental health treatments;
multiple trials are underway assessing impact on a variety of physical health conditions
including osteoporosis, insulin resistance, and cardiovascular risk. A large scale
epidemiologic RCT (the Vitamin D and omega¬3 Trial; VITAL) is examining whether supplementation
prevents chronic diseases (http://www.vitalstudy.orgwebcite).

Supplementation issues in adolescents

How should low vitamin D levels be corrected? Supplementation with over-the-counter
or prescription vitamin D for those with low vitamin D is important, as natural dietary
sources are few and include chiefly oily fish, irradiated mushrooms, egg yolks, and
fortified milk, juices, cereal, and margarine (http://dietary¬supplements.info.nih.gov/factsheets/vitamind.aspwebcite). Most adolescents, especially those who skip breakfast or are lactose intolerant,
do not consume adequate amounts of these foods to maintain optimal vitamin D levels,
and cannot meet their requirements through diet alone. Risk for developing vitamin
D toxicity with supplements has been largely unsupported [34]; studies giving as much as 14,000 IU per week of D3 to adolescents over one year’s
time have shown no evidence of toxicity [35]. A serum level of more than 200 ng/ml 25-OHD may be necessary for symptoms of toxicity
to occur. The Institute of Medicine in 2010 raised its daily intake recommendations
based on evidence for skeletal growth and maintenance; the current recommended dietary
allowance (RDA) is 600 IU per day for 1–70 years of age with an upper level intake
of 4,000 IU per day [36]. The American Academy of Pediatrics had previously raised its recommended supplementation
from 200 IU in 2003 to 400 IU per day in 2008 to prevent rickets in children and adolescents
who do not obtain this goal through fortified foods [37]. Additional initial supplementation to return deficient individuals to normal may
be indicated as dietary reference intake amounts recommended by the IOM may still
be insufficient for bone health maintenance in many individuals [38]. The amount necessary to prevent breast and colon cancer, Type I diabetes, and multiple
sclerosis has been speculated to be closer to 4,000-8,000 IU per day [32]. The amount appropriate for maintenance of best mental and physical health is therefore
controversial, and is unknown in the chronically mentally ill, who may metabolize
vitamin D more quickly due to added oxidative stress burden.

Limitations

This work is limited by a small sample size, cross-sectional method, inpatient sampling
bias, and lack of formal research measures for diagnosis and severity of illness,
family psychiatric history, sun exposure, and intake of Vitamin D and other dietary
nutrients. No adolescents, however, were taking vitamin D supplementation. A winter
sampling bias is present, potentially contributing to low rates of D-deficiency, however,
this does not rule out that seasonal effects in illness severity and admission rates
related to greater vitamin D deficiency may occur. Analysis of ultraviolet radiation
for latitudes 0 to 80 degrees N found that for March through October, sites from 18
degrees to 44 degrees N (the majority of the continental United States) had equal
amounts of vitamin D producing ultraviolet light; November through February only demonstrated
decreases in vitamin D producing ultraviolet light [39]. Additional limitations include that adolescents were not screened for osteomalacia;
serum parathyroid hormone values were not routinely checked in those who were D-deficient;
however, several performed clinically were within normal ranges. Many confidence intervals
are wide; confirmation of these results awaits a large sample study and more rigorous
design. Probing smaller enriched clinical samples may be useful in providing biologic
signals of relevance in populations with depression, for example, using neurocognitive
tasks. Descriptive differences in a clinical population compared with population norms
may also provide direction for further investigation related to both interactive effects
of mental illness and ancestry.

Conclusion

Vitamin D deficiency is highly prevalent in this descriptive sample of acutely mentally
ill adolescents, especially in African-American and Asian teens, and appears related
to psychotic symptoms. This work is the first to report an association between psychosis
and vitamin D deficiency in psychiatrically hospitalized adolescents [40] and confirms this association found previously in an adult population [13]. Our study also expands on similar deficiency findings from a Parisian inpatient
adolescent cohort [15], providing clinical diagnoses of mood disorders in the great majority of inpatient
teens with vitamin D deficiency, and further, finding lower risk for psychosis in
the presence of antidepressant treatment. Both support the possibility that heightened
vulnerability to psychotic features occurs in the substantial proportion of teens
with mood disorders who are vitamin D deficient. Prospective trials of vitamin D supplementation
are needed to address targeted mental health symptom domains as well as metabolic
health variables in D-deficient severely mentally ill adolescents and adults, focusing
on dose-finding and tolerability. Calls have been made for clinical monitoring in
patients with psychiatric illness as well as randomized trials of vitamin D for depression
[41,42]. Clinical screening for vitamin D deficiency in severely mentally ill adolescents
is justified by their high risk for both chronic mental illness and early onset of
cardiometabolic comorbidities, especially as vitamin D deficiency at mid-life appears
a strong independent predictor of all-cause mortality (odds ratios 2.64, 95% CI 1.901
to 3.662. p < 0.0001) [43]. A key clinical question raised by our work and supported by known safety data is
whether psychiatrically hospitalized dark-complected adolescents, including African-Americans,
Asians, and Muslim females in traditional covered dress, should be routinely supplemented
with vitamin D until proven otherwise.

Competing Interests

The authors declare that they have no competing interests.

Authors’ Contributions

BLG conceptualized the study, designed the methodology and implementation, interpreted
data, and wrote the report. TLF designed the data collection forms, performed the
blinded chart review, and assisted in preparing background information. MCF and MP
assisted in collecting data. SM provided statistical analysis. All authors read and
approved the final manuscript.

Acknowledgements

This work was supported by the Jeffrey Research Fellowship, Nationwide Children’s
Hospital/The Ohio State University, and the University of Rochester Clinical Translational
Science Institute/Grant Number 1 KL2 RR024136-1 from the National Center for Research
Resources (NCRR), a component of the National Institutes of Health (NIH), and the
NIH Roadmap for Medical Research. Its contents are the sole responsibility of the
authors and do not necessarily represent the official view of NCRR or NIH. Information
on NCRR is available at http://www.ncrr.nih.gov/. Information on Re-engineering the Clinical Research Enterprise can be obtained from:
http://nihroadmap.nih.gov/clinilcalresearch/overviewtranslational.asp